Use of cis-or transurocamic acid for the treatment of photodermatoses and immunogenic skin diseases

ABSTRACT

A compound of the general formula (I): Q--R--X wherein Q is a substituted or unsubstituted furanyl, imidazolyl, pyrrolyl or thiopheneyl group, R is CR 1   2  --Cr 2   2 , (cis)CR 1  ═CR 2 , or (trans)-CR 1  ═CR 2 , X is COOR 3  or NR 1  R 4 , and R 1  -R 4  are each, independently, H, an alkyl or an aryl group and pharmaceutically acceptable salts thereof, are described for use in topical treatments of skin conditions which involve an overactive immune response, or which are responsive to UV irradiation. Pharmaceutical compositions of the compound of general formula (I) are also described.

DESCRIPTION

The present invention relates to compounds of general formula I:

    Q--R--X                                                    (I)

wherein Q is a substituted or unsubstituted furanyl, imidazolyl,pyrrolyl or thiopheneyl group, R is CR¹ ₂ --CR² ₂, (cis)CR¹ ═CR², or(trans)CR¹ ═CR², X is COOR³ or NR¹ R⁴, and R¹ -R⁴ are each,independently, H, or an alkyl or an aryl group and to pharmaceuticallyacceptable salts thereof. The invention also relates to the use of suchcompounds in the topical treatment of skin conditions considered toinvolve an over-active immune response, or which are responsive toultraviolet (UV) radiation.

Trans-urocanic acid (UCA) is a naturally occurring compound found in theupper layers of the epidermis, where it is synthesized throughdeamination of histidine by histidase. When the skin is irradiated withultraviolet light, up to 60 or 70% of the trans-UCA present is convertedinto the cis-isomer and it is thought that cis-UCA, once so generated,functions as a mediator in both systemic and local UV induced immunesystem suppression. See the review article by M. Norval et al. inPhotochemistry and Photobiology Vol. 50. No. 2, pp 267-275, 1989 (1).

Support for the proposition that cis-UCA is a mediator in UV inducedsuppression of the immune system is provided by the work reported by M.Norval et al. in Photochemistry and Photobiology Vol. 49. No. 5, pp633-639, 1989 and that of V. E. Reeve et al., reported in PhotodermatolPhotoimmunol Photoreed 1991: 8: pp 176-180. The former authors foundthat cis-UCA was able to induce suppression of normal delayed typehypersensitivity response to herepes simplex virus type 1 in mice andthe latter found that cis-UCA, generated by applying trans-UCA (in acosmetic cream) to murine skin and then irradiating the treated skin,systemically suppressed normal contact hyper-sensitivity. Reeve et al.suggested that this activity is potentially harmful, since it couldresult in tumour development and, therefore, concluded that urocanicacid was potentially hazardous and should not be used as a cosmeticingredient. Indeed, Reeve et al., in Photochemistry and PhotobiologyVol. 49. No. 4. pp 459-464. 1989., reported that topically appliedtrans-UCA significantly increased the tumour load induced in hairlessmice, on exposure to Erythema inducing doses of UV light or sunlight.

Thus, rather than being confirmed as therapeutically useful,investigation of their metabolic roles has led to the removal oftrans-UCA from various commercially available cosmetic creams (seeConcar in the New Scientist, May 16, 1992), to obviate the risk of itbeing transformed into the apparently harmful cis-isomer, and to cis-UCAbeing considered of potential use only in the treatment of serious orlife-threatening conditions, such as those involving transplant surgery,etc. For example, cis-UCA has been suggested as a possibleimmuno-suppressive agent for use in transplant surgery, particularly inskin grafting.

However, contrary to the indications discussed above, it has now beenfound that certain UCA isomers, derivatives and analogues can betherapeutically useful. Accordingly, the present invention provides acompound of general formula I

    Q--R--X                                                    (I)

wherein Q, R and X are as hereinbefore defined, or a pharmaceuticallyacceptable salt thereof, for use in a topical treatment of a skincondition which involves an over active immune response or which isresponsive to UV radiation.

In preferred embodiments of the invention, a compound of general formula(I) can be for use in a method of treating photodermatoses includingpolymorphic light eruption, photosensitivity, dermatitis/actinicreticuloid syndrome, actinic prurigo and solar urticaria; generalurticarias of allergic and non-allergic type; contact sensitivity andskin diseases that respond to UV radiation including, acne vulgaris,alopecia areata, dermatitis herpetiformis, eosinophilic pustularfolliculitis, erythrokeratoderma (symmetrical and progressive), chroniclichenoid GVH disease, granuloma annulare, histiocytosis X, ichthyosislinearis circumflexa, lichen planus, pityriasis lichenoides, pityriasisrosea, pityriasis rubra pilaris, pressure sores, pruritis (primary andsecondary), seleromyxoedema, subcorneal pustular dermatoses, transientacantholytic dermatoses, psoriasis and atopic eczema. The invention,preferably, can relate to just one or a selection of the aforementionedconditions.

The invention further extends to a method of treating a skin conditionconsidered to involve an over active immune response, or a conditionresponsive to UV irradiation, inclusive of the specific conditionslisted above, or just one or a selection of these conditions.

In a third aspect, the invention provides the use of a compound ofgeneral formula (I), as hereinbefore defined, for the manufacture of amedicament for use in the treatment of any one, a selection, or all ofthe conditions defined, or listed above.

In a further aspect, the present invention provides a pharmaceuticalcomposition, comprising a compound of general formula (I), ashereinbefore defined, in admixture with a pharmaceutically acceptableexcipient or carrier and suitable for topical use. Preferably, saidcomposition is for use in treating a condition as hereinbefore definedor listed above.

In embodiments of any aspect of the invention, Q, in general formula(I), can be substituted with F, Cl, Br or --CH₃ but, preferably, isunsubstituted; R¹ -R⁴ each, independently, can be H, a lower alkyl group(preferably C₁ -C₄) or a phenyl group but, preferably, are H; and R,preferably, is (cis)CR¹ ═CR².

In all aspects and embodiments of the invention, the preferred compoundgeneral formula (I) is cis-UCA. However, the invention encompasses thetopical application of trans-UCA and its conversion, in situ, to cis-UCAby irradiation with UV light. The necessary UV light can be providedfrom an artificial source or by exposure to sunlight. Preferably, the UVis provided using an artificial source.

Preferred pharmaceutical compositions, in accordance with the presentinvention, comprise ointments, gels, aerosols, wipes, creams, lotions oremulsions which include a compound of general formula I, in admixturewith a suitable carrier, mixture of carriers or emulsion thereof.

Cis-UCA can be prepared from the trans-isomer which is available fromSigma UK Ltd. (Poole, Dorset, UK). To prepare the cis-isomer, a solutionof trans-UCA at a concentration of 10 mg/ml in dimethyl sulphoxide (ormethanol) is spread thinly and irradiated under two Phillips TL20W/L UVlamps for three hours, which provide a total dose of 864 mj/cm2 in therange 270-350 nm. The conversion rate of trans-UCA to cis-UCA is in theorder of 70%. Thus, all compositions and preparations, in accordancewith the invention, which include cis-UCA can also include trans-UCAand, where quantities of cis-UCA are mentioned, a proportion thereof canbe trans-UCA.

Methods of synthesizing other compounds of formula I are set out in M.Norval et al., Photochemistry and Photobiology Vol. 49. No. 5. pp633-639. 1989.

Pharmaceutical compositions may be prepared by incorporating cis-UCA,prepared in the manner discussed above, into a conventionalpharmaceutical cream or other suitable base, using conventionaltechniques known in the art.

The following examples are provided by way of illustrative embodimentsand are not intended in any way to limit the scope of the invention.

EXAMPLE 1

Gel Composition

100 g of a gel composition, suitable for topical application to theskin, were prepared from the following quantities of the followingsubstances;

    ______________________________________                                        cis-UCA                      1.0 g                                              Hydroxyethyl cellulose                   2.0 g                                Nipasept Sodium                        0.15 g                                 Glycerol                                 l0 g                                 Water                       to         l00 g.                               ______________________________________                                    

The hydroxyethyl cellulose used was Cellosize QP52, OOOH and wasemployed as a viscosity enhancer, as well as to provide the compositionwith the required gel characteristics.

The cis-UCA was prepared from trans-UCA by irradiating a thinly spreadsolution of 1.0 g of trans-UCA, in dimethyl sulphoxide (10 mg/ml), withtwo Phillips TL 20 w/l UV lamps for three hours. The conversion rate oftrans-UCA to cis-UCA was approximately 70% and, therefore, the cis-UCAused contained up to about 30% trans-UCA. After irradiation, theremaining solvent was removed by evaporation and the cis-UCA wasdissolved in a portion of the water. The remaining components were thenmixed into the resulting solution and the rest of the water was added toform the final gel.

EXAMPLE 2

Cis-UCA, formed by the irradiation method set out in Example 1, wasmixed into a jelly formed from 50% white soft paraffin and 50% liquidparaffin at a concentration of about 2% w/w. The resulting compositionwas suitable for topical application to the skin.

EXAMPLE 3

Non-aqueous Spray

Non-aqueous sprays in accordance with the invention can be preparedusing the following materials in the proportions set out below:

    ______________________________________                                                               % w/v                                                  ______________________________________                                        cis-UCA                      0.1-5                                              isopropyl isostearate                     10-40                               cyclomethicone                           10-40                                Azone                                      0-20                               oil (preferably coconut)      to         100                                ______________________________________                                    

The preferred composition for such a spray is 2% cis-UCA, 30% isopropylisostearate, 30% cyclomethicone, 5% azone and 33% coconut oil (all%/w/v).

EXAMPLE 4

Gel Composition

Further gels in accordance with the invention can be prepared using thefollowing materials in the proportions set out below:

    ______________________________________                                                               % w/w                                                  ______________________________________                                        cis-UCA                                                           0.1-10                                    Sodium carboxymethy  1.5-2.5                      cellulose                                                                     Sorbic acid                                  0.75                             Propylene glycol                             2.0-25                           Buffering agent                             0.01-1                            Purified Water                   to        100                              ______________________________________                                    

The preferred composition for such a gel is 5% cis-UCA, 2% sodiumcarboxymethyl cellulose, 0.75% sorbic acid 10% propylene glycol, 0.1%buffering agent and purified water to 100% (all %w/w).

EXAMPLE 5

Cream Composition

Creams in accordance with the invention can be prepared using thefollowing materials in the proportions set out below:

    ______________________________________                                                 cis-U               0.1-10                                             Cosmowax                                 10-25                                Oleyl Alcohol                             0.1-10                              Oleic Acid                                0.1-10                              Liquid Paraffin                           5-25                                Polysorbate 20                            0.1-5                               Phenonip                                  0.1-1                               Buffering Agent                           0.1-1                               Sorbic Acid                               0.075                               Purified Water         to              100                                  ______________________________________                                    

The preferred composition for such a cream is 5% cis-UCA, 15% cosmowax,3% oleyl alcohol, 2% olecic acid, 15% liquid paraffin, 1% polysorbate20, 0.5% phenonip, 0.1% buffering agent, 0.075% sorbic acid and water to100%.

EXAMPLE 6

Paint Composition

Paints in accordance with the invention can be prepared using thefollowing materials in the proportions set out below:

    ______________________________________                                                               % w/v                                                  ______________________________________                                        cis-UCA                      0.1-10                                             Purified Water                              0-60                              Dimethyl Sulphoxide        To             100                               ______________________________________                                    

The preferred composition for such a paint is 5% cis-UCA, 20% purifiedwater and 75% dimethyl sulphoxide.

We claim:
 1. A pharmaceutical composition comprisinga topicalpreparation of a compound of general formula I, or a pharmaceuticallyacceptable salt thereof:

    Q--R--X                                                    (I)

wherein Q is a substituted or unsubstituted pyrrolyl group, R is CR¹ ₂--CR² ₂, (cis)CR¹ ═CR², or (trans) --CR¹ ═CR², X is COOR³ or NR¹ R⁴, andR¹ -R⁴ are each independently, H, or an alkyl or an aryl group, in anamount for therapeutic treatment of a skin condition which is responsiveto UV irradiation and is selected from the group consisting ofpolymorphic light eruption, actinic purrigo, solar urticaria acnevulgaris, alopecia areata, dermatitis herpetiformis, eosinophilicpustular folliculitis, erythrokeratoderma, chronic lichenoid GVHdisease, granuloma annulare, histiocvtosis X, ichthyosis lineariscircumflexa, lichen planus, pityriasis lichenoides, pityriasis rosea,pityriasis rubra pilaris, subcorneal pustular dermatoses, transientacantholytic dermatoses, psoriasis and atopic eczema.
 2. Thepharmaceutical composition of claim 1, wherein Q is unsubstituted, orsubstituted with F, Cl, Br, or CH₃.
 3. The pharmaceutical composition ofclaim 1, wherein R¹ -R⁴ each, independently, are H, a lower alkyl groupor a phenyl group.
 4. The pharmaceutical composition of claim 1, whereinR is (cis)CR¹ ═CR².
 5. The pharmaceutical composition of claim 1,wherein Q is unsubstituted.
 6. The pharmaceutical composition of claims1, 4 or 5, wherein R¹ -R⁴ are each H.
 7. The pharmaceutical compositionas claimed in claims 1, 2, 3, 4, 5 or 6, in admixture with apharmaceutically acceptable excipient or carrier suitable for topicaluse.
 8. The pharmaceutical composition of claim 7 comprising anointment, gel, aerosol, wipe, cream, lotion or emulsion.
 9. A method fortreating a skin condition which is responsive to UV irradiation and isselected from the group consisting of polymorphic light eruption,actinic purrigo, solar urticaria, acne vulgaris, alopecia areata,dermatitis herpetiformis, eosinophilic pustular folliculitis,erythrokeratoderma, chronic lichenoid GVH disease, granuloma annulare,histiocytosis X, ichthyosis linearis circumflexa, lichen planus,pityriasis lichenoides, pityriasis rosea, pityriasis rubra pilaris,subcorneal pustular dermatoses, transient acantholytic dermatoses,psoriasis and atopic eczema, comprising:topically applying to a subjectin need of such treatment a therapeutic amount of the compound of claim1, 2, 3, 4, 5 or
 6. 10. The method of claim 9 wherein the compound is inan admixture with a pharmaceutically acceptable excipient or carrier.11. The method of claim 10 wherein the compound is in an ointment, gel,aerosol, wipe, cream, lotion or emulsion.
 12. A pharmaceuticalcomposition comprising a topical preparation of a compound of generalformula I, or a pharmaceutically acceptable salt thereof:

    Q--R--X                                                    (I)

wherein Q is an unsubstituted pyrrolyl group, R is (cis)CR¹ ═CR², and R¹and R² are both H, in an amount for therapeutic treatment of a skincondition which is responsive to UV radiation and is selected from thegroup consisting of polymorphic light eruption, actinic prurigo, solarurticaria, acne vulgaris, alopecia areata, dermatis herpetiformis,eosinophilic pustular folliculitis, erythrokertoderma, chronic lichenoidGVH disease, granuloma annulare, histiocytosis X, ichthyosis lineariscircumflexa, lichen planus, pityriasis lichenoides, pityriasis rosea,pityriasis rubra pilaris, subcomeal pustular dermatoses, transientacantholytic dermatoses, psoriasis and atopic eczema.
 13. Thepharmaceutical composition of claim 12 which includes a pharmaceuticallyacceptable excipient or carrier suitable for topical use.
 14. Thepharmaceutical composition of claim 13 wherein the compound of generalformula I is present in an amount of from about 0.1% w/w to about 10%w/w.